SUMMARY The overall hypothesis of this proposal is that Ubiquilin1 suppresses critical signaling pathways that drive the pathogenesis of both Alzheimer's disease and cancer. These two diseases represent two of the largest burdens on the healthcare systems in all developed countries. In the U.S. the annual national expenditure for these two diseases combined is ~$300 billion dollars. Currently in the U.S. there are ~5.4 million people living with Alzheimer's disease and there will be ~1.7 million new cancer cases diagnosed this year. Only by understanding the basic molecular, biochemical and genetic causes of these diseases will we be able to make significant progress in treating these patients. Interestingly, it has been reported, but largely ignored, that there are common signaling pathways that are altered to drive the onset of both Alzheimer's disease and cancer. This proposal seeks to understand how the of scaffold protein, Ubiquilin1, regulates seemingly opposing cellular outcomes in epithelial cells and neuronal cells. Loss of Ubiquilin1 in epithelial cells increases proliferation and migration, whereas in neuronal cells, it causes cell death. Amazingly, there are a number of additional signaling pathways that behave in a similar cell-type and context-dependent manner, including amyloid precursor protein (APP), growth factor receptors (such as IGF1R) and focal adhesion complexes, such that aberrant activation of processes contributes to both tumorigenic phenotypes, as well as progression of Alzheimer's disease. We are the first to show that loss of Ubiquilin1, as seen in cancer and Alzheimer's disease, causes increased growth factor receptor signaling and increased focal adhesion formation and signaling. In this proposal we will examine the detailed molecular and biochemical regulation of these processes by Ubiquilin1 and we will examine the cell-type and context-dependent differences of Ubiquilin1 function in epithelial and neuronal cells. This information will shed light on the basic mechanisms that contribute to multiple diseases afflicting millions of people every year.